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Figure 2. Schematic of the roles of α-syn in autophagy in PD. In the physiological state, macroautophagy and CMA pathways are involved in α-syn degradation (monomeric, dimeric, and tetrameric forms). In pathological conditions of PD, SNCA mutations contribute to the pathological aggregation of α-syn, such as oligomer, fibrosis, and Lewy body forms, which leads to impairments of autophagy and CMA pathways. Pathological aggregated α-syn interferes with autophagosomal formation, blocks the fusion of autophagosomes with lysosomes, and impairs the lysosomal activity. Additionally, mutants or other posttranslational modifications of α-syn bind with LAMP2A with high affinity, blocking the degradation of other substrates in the CMA pathway and resulting in lysosomal dysfunction. Impaired autophagy and CMA further exacerbate the aggregation of pathological α-syn, subsequently leading to the death of dopaminergic neurons. Furthermore, under conditions of lysosomal dysfunction, autophagic impairment, and proteasome inhibition, pathological α-syn serves as a seed that spreads to surrounding neurons, leading to more neuronal death. α-syn: α-synuclein; PD: Parkinson’s disease; CMA: chaperone-mediated autophagy; SNCA: α-syn-encoding gene; LAMP2A: lysosome-associated membrane protein 2A.